tbuckley/cabot-search huggingface dataset:
MODL-21. INVESTIGATING THE PATHOGENIC MECHANISMS OF FOXR2-MUTATED PEDIATRIC BRAIN TUMOR USING A HUMAN-EMBRYONIC STEM CELL-BASED MODEL
Authors: Hitomi Royston, Miriam Emerson, Autumn Hampton, Kosuke Funato
Journal: Neuro-Oncology (2023)

Abstract FOXR2-activated CNS neuroblastoma is a recently identified subtype of brain tumor characterized by genomic rearrangements at the FOXR2 locus and elevated expression of the transcription factor FOXR2. However, the precise mechanisms underlying the tumorigenesis of this specific subtype, including the cell type of origin, are not fully understood. In this study, we established a new tumor model using human embryonic stem cells (hESCs) to determine the cell type of origin and the underlying pathogenic mechanisms. Expression profile analysis of patient tumors revealed increased expression of interneuronal marker genes, such as DLX1, NKX2.1, and SST (Somatostatin). Given that NKX2.1 and SST are markers for interneuronal cells originating from the Medial Ganglionic Eminence (MGE) in the ventral forebrain, we hypothesized that MGE-derived interneuronal progenitors are the cell type of origin. To test this hypothesis, we differentiated hESCs into MGE-type interneuronal progenitors using a chemically defined protocol, while using cortical excitatory neural progenitors as a control cell type. Subsequently, we overexpressed FOXR2 in these cell populations and analyzed the cellular phenotype. Our data showed that, in low density culture, FOXR2 overexpression in the MGE-type interneuronal progenitors led to a significantly greater increase in proliferation compared to the cortical progenitor cells, indicating a cell-type-specific effect of FOXR2. Our novel model holds great promise for elucidating the molecular mechanisms underlying the formation of FOXR2-activated CNS neuroblastoma and paving the way for the discovery of therapeutic targets and effective treatments for patients suffering from this devastating disease.
NCMP-11. ASSESSING SURVIVAL OUTCOMES OF PCV-BASED AND TEMOZOLOMIDE-BASED ADJUVANT THERAPY IN OLIGODENDROGLIOMA PATIENTS
Authors: Sabrina Begley, Adrian Chen, Michael Schulder, Anuj Goenka
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION When treating oligodendroglioma, choosing between temozolomide (TMZ) and procarbazine, lomustine, and vincristine (PCV), with concurrent radiotherapy still poses a challenge. Given the commonality of tumor recurrence, optimizing progression-free survival while minimizing adverse effects is crucial to improving quality of life. We compare survival and adverse effects of patients treated for oligodendroglioma with PCV-based vs TMZ-based adjuvant therapy. METHODS 87 patients treated for oligodendroglioma between 1994-2022 were retrospectively reviewed. Progression-free survival (PFS) and overall survival (OS) from initial resection were compared between PCV-based or TMZ-based treatment groups using Kaplan-Meier and multi-variable Cox survival analysis. RESULTS The median age at diagnosis was 41 years and 62% were male. After initial resection, 42.8% received PCV-based treatment and 57.2% received TMZ-based treatment. Treatment groups were balanced in the following variables: age, tumor genetic profiling, extent of resection, and KPS score. However, more patients in the TMZ-based group received concurrent radiation. The entire cohort had a 6.3-year PFS and 21.0-year OS. The median time to recurrence was significantly longer in those treated with PCV (12 years) compared to those treated with TMZ (4.7 years). PFS [HR = 0.46, p = 0.04] and OS [HR = 0.26, p = 0.04] were significantly longer in those receiving PCV-based treatment compared to TMZ-based treatment (Fig. 1). After adjusting for aforementioned variables, Cox regression analysis revealed no difference in OS between PCV- and TMZ-based treatment. The overall adverse effect rate did not significantly differ between PCV-based and TMZ-based treatment (25% vs. 28.1%, p &amp;gt; 0.99). CONCLUSIONS PCV treatment confers longer progression-free survival than TMZ treatment for oligodendroglioma patients, noting that most patients in our series received concurrent radiation with TMZ, and those receiving PCV not having received upfront radiation. Pending clinical trial results, our findings suggest PCV-based therapy warrants consideration as the preferred therapeutic option for oligodendroglioma patients.
TMIC-29. BEVACIZUMAB IS ASSOCIATED WITH INCREASED RATE OF RECURRENCE IN GLIOBLASTOMA
Authors: Mahlet Mekonnen, Sanah Vohra, Anubhav Chandla, Yelena Malkhasyan, Isaac Yang
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The primary cause of Glioblastoma’s (GBM) dismal outcomes is the high rate of tumor recurrence, which is closely related to its resistance to standard therapies. Bevacizumab has increasingly been used in the treatment of recurrent GBM. However, the data on Bevacizumab has been mixed regarding its efficacy in improving patient survival. Moreover, there is no conclusive evidence in the literature regarding Bevacizumab treatment and its association with increased incidence of distant or diffuse recurrence. Objective: To provide conclusive evidence on the recurrence rate associated with Bevacizumab treatment in GBM patients METHODS UCLA GBM patients were reviewed for recurrence pre-and post-Bevacizumab treatment. Patients whose Bevacizumab treatment was not flanked by surgeries and patients with only one surgery were excluded. After exclusion criteria were applied, 94 patients were included in the results. The number of recurrences preceding and following Bevacizumab was recorded. RESULTS In a cohort of 94 patients, the average recurrence rate pre-Bevacizumab treatment was 0.29 ± 0.88, whereas the average recurrence rate post-Bevacizumab treatment was 2.51 ± 1.64. Overall, the recurrence rate was significantly higher in GBM patients post-Bevacizumab treatment (95% CI [1.83, 2.59]; p&amp;lt; 0.0001). CONCLUSION Our results suggest that Bevacizumab treatment is associated with an increased rate of recurrence. This finding is indicative of tumor transition to a more aggressive phenotype that is associated with Bevacizumab treatment.
NCOG-24. RISK-ADAPTED TREATMENT STRATEGIES WITH PRE-IRRADIATION CHEMOTHERAPY IN PEDIATRIC MEDULLOBLASTOMA: OUTCOMES FROM THE POLISH PEDIATRIC NEURO-ONCOLOGY GROUP
Authors: Anne Cochrane, Marta Perek-Polnik, Jinli Wang, M Chojnacka, M Drogosiewicz, I Filipek, E Swieszkowska, M Tarasinska, P Kowalczyk, Mohamed S Abdelbaki, Bożenna Dembowska-Bagińska
Journal: Neuro-Oncology (2023)

Abstract Craniospinal irradiation (CSI) has been a major component of the standard of care treatment backbone of childhood medulloblastoma. However, chemotherapy regimens have varied based on protocol, patient age, and molecular subtyping. In one of the largest studies to date, we analyze treatment outcomes in children with newly-diagnosed medulloblastoma treated with pre-irradiation chemotherapy followed by risk-adapted radiotherapy and maintenance chemotherapy. A total of 153 patients from the Polish Pediatric Neuro-oncology Group were included in the analysis. Median age at diagnosis was 8.0 years. Sixty-seven patients were classified as standard risk and 86 as high risk. Overall survival (OS) and event-free survival (EFS) for standard-risk patients at 5 years (± standard error) were 87 ± 4.3% and 84 ± 4.6% respectively, while 5-year OS and EFS for high-risk patients were 81 ± 4.3% and 79 ± 4.5% respectively. This study demonstrates promising survival outcomes in patients treated with pre-irradiation chemotherapy followed by risk-adapted CSI and adjuvant chemotherapy. Such an approach may be useful in cases where initiation of radiotherapy may need to be delayed, a common occurrence in many institutions globally.
INNV-14. INTERIM REPORT OF A PHASE 1/2 STUDY OF SONODYNAMIC THERAPY (SDT) USING AMINOLEVULINIC ACID (ALA) AND LOW-INTENSITY FOCUSED ULTRASOUND IN PEDIATRIC PATIENTS WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Hasan Syed, Lindsay Kilburn, Roger Packer, Robert Keating, Sabine Mueller, Nirali Patel, Peter Fenn, Ryan Clanton, Corina Andresen, Stuart Marcus, Ely Benaim
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND DIPGs are devastating pediatric brain tumors with limited treatment options, poor prognosis, and survival of 9-11 months. Preclinical studies demonstrate that performing SDT through MR-guided focused ultrasound (MRgFUS) activates ALA metabolite, protoporphyrin IX (PpIX), leading to tumor cell death and prolonging survival in rodent glioma models through generation of reactive oxygen species and lipoperoxidation, without affecting normal tissue. MEDTHODS: Herein we report preliminary data from an ongoing first-in-child dose-escalation trial of ALA-SDT post-radiation therapy in children ≥ 5 years with DIPG. The trial aims to evaluate the safety and tolerability of ALA-SDT, determine the recommended-phase-2-dose and assess preliminary efficacy and pharmacokinetics (PK) of ALA administered intravenously. RESULTS The first study cohort completed enrollment of 3 subjects. Six hours prior to SDT, patients received an infusion of ALA (SONALA-001) at a dose of 5 mg/kg, followed by sonication with 200J. The first subject was treated in 2 sessions: each to half of the pons 30 days apart. Two subsequent subjects had the entire pons treated in a single session. No dose-limiting toxicity (DLT) or related adverse event grade ≥ 3 were observed. For SONALA-001, the Cmax occurred at the end of infusion, followed by rapid clearance (15.7 mL/min/kg), with a plasma half-life of &amp;lt; 1 hour, indicating rapid distribution (5530 ml/kg). For PpIX, the Cmax occurred 6 hours post-dose and declined with a longer mean half-life of 3.8 hours. Both Cmax and AUCall demonstrate circulating PpIX and systemic exposure were significantly lower than for ALA. CONCLUSION SDT signals an innovative and well-tolerated approach for patients with DIPG in our first study cohort. As expected, the PK for SONALA-001 demonstrate rapid infusion and clearance, whereas for PpIX, the PK are consistent with formation of a metabolite. Clinical trial enrollment is ongoing and dose-escalation cohorts will provide additional PK and safety data.
CNSC-40. HARNESSING EVOLUTIONARY CONSTRAINT IDENTIFIES POTENTIAL NON-CODING DRIVERS IN BRAIN TUMORS
Authors: Ananya Roy, Raphaela Pensch, Sharadha Sakthikumar, Sergey V Kozyrev, Jessika Nordin, Suvi Mäkeläinen, Ylva Jansson, Mats Pettersson, Elinor Karlsson, Kerstin Lindblad-Toh, Karin Forsberg-Nilsson
Journal: Neuro-Oncology (2023)

Abstract The somatic mutational landscape of brain tumors has primarily focused on coding mutations for driver gene discovery. Non-coding mutations can drive cancer by targeting regulatory elements and be valuable biomarkers and therapeutic targets. However, their identification and functional impact have been elusive. Here, we apply evolutionary constraint (phyloP scores, a constraint metric from sequence alignment of 241 mammals) to whole genome sequencing data from three different brain tumors; pilocytic astrocytoma (PA), medulloblastoma (MB), and glioblastoma (GBM) to identify non-coding constraint mutations (NCCMs) with regulatory potential. NCCM rates (phyloP ≥ 1.2) differ significantly between these cancers, with low rates of NCCMs in PA reflecting its benign feature and high rates in MB and GBM, in support of their aggressivity and heterogeneity. Many of the NCCMs affect genes that are developmentally regulated and expressed in the brain, hence they could be potential drivers. In PA, a high NCCM frequency only affects the BRAF locus, while in MB, over 500 genes have high levels of NCCMs. Intriguingly, many of these genes are associated with different age of onset, such as NUAK1 in adult patients and HOXB1 in young patients, pointing to different molecular pathways in patient groups. NCCMs in the HOXB locus altered the expression of multiple genes of the cluster in MB cells. In GBM NCCMs with regulatory potential cluster as hotspots in PTEN, LRFN5 and MIR99AHG. We observe an enrichment of NCCMs in the regulatory regions of transcription factors including FOXA1, HOXA9 and EBF1. We conclude that since evolutionary constraint is agnostic to cell type or disease stage, it is a powerful predictor of function. Understanding changes in the non-coding cancer genomes will lead to more robust patient stratification of future treatment.
PATH-50. GENETIC AND EPIGENETIC PROFILING OF MENINGIOMAS TO GAIN INSIGHTS INTO MOLECULAR HETEROGENEITY AND RISK STRATIFICATION.
Authors: Vaishali Suri, Jyotsna Singh, Ashish Suri, M C Sharma
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Meningiomas are slow-growing CNS tumors, with most being benign (WHO grade 1) and having indolent behavior. Limited data on molecular profiling of meningiomas and its clinical implications have hindered the implementation of effective therapies and new treatments. Aims &amp; Objectives: Perform DNA methylation profiling, copy number analysis, and targeted sequencing in meningiomas. MATERIALS &amp; METHODS 208 meningiomas, grade 1 (n=109), grade 2 (n=83), and grade 3 (n=16)were assessed for pTERT mutation, CDKN2A homozygous deletion, and H3K27me3 expression. Additionally, 35 diagnostically challenging meningiomas underwent DNA methylation profiling, copy number analysis, and targeted sequencing. RESULTS there were 199 adult and 9 pediatric cases, (mean age 44.5 years). The tumors were located in basal (53%) ,convexity (42%),and 5% in other locations.pTERT C228T mutation was detected in 4.8% and CDKN2A deletion in 2.4% cases. Loss of H3K27me3 expression was found in a significant proportion of tumors across all three grades. Methylation profiling identified four distinct molecular subgroups: Malignant, Intermediate, Benign A, and Benign B. Intermediate, Benign A, and Benign B subgroups included both WHO grade 1 and grade 2 cases. Mutations showed a strong association with specific methylation subgroups (NF2, AKT1, SMO, TRAF7, and pTERT). Loss of chromosome 22q was observed in all subgroups. 1p/14q co-deletion was predominantly seen in the malignant and intermediate subgroups (50%). CDKN2A loss was mainly observed in the malignant subgroup (50%). The DKFZ classifier successfully classified 71% of cases with an acceptable score. Methylation profiling significantly influenced PFS in WHO grade 1 and 2 meningiomas (p=0.0051). CONCLUSIONS Genome-wide DNA methylation profiling reveals clinically distinct molecular subgroups and heterogeneity within the same grade of meningiomas and is particularly valuable for identifying high-risk cases and predicting prognosis in WHO grade 1 and 2 meningiomas. The pTERT mutation serves as a significant and cost-effective marker for risk stratification in meningiomas.
RADT-30. PROTON THERAPY FOR RE-IRRADIATION OF RECURRENT GLIOMA
Authors: Andrew Barbour, Lia Halasz
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Proton therapy may improve the side effect profile of re-irradiation for recurrent glioma by limiting the overlap with previous radiation dose received by the brain. Limited data exist regarding the outcomes or side effects after proton re-irradiation. METHODS We retrospectively reviewed the charts of 43 consecutive adult patients with glioma treated with uniform scanning or pencil beam scanning proton re-irradiation from June 2014-June 2022. Outcomes were estimated utilizing Kaplan-Meier analysis. RESULTS Median age of the cohort was 45 years (range 19-74). Initial histologic diagnosis was glioblastoma for 18 (42%), astrocytoma for 16 (37%), oligodendroglioma for 8 (19%) and diffuse glioma NOS for 1 (2%) patient. The median initial prescription dose was 60 Gy (range 54-61.2 Gy) with 86% receiving concurrent temozolomide. The median interval between initial radiation therapy (RT) and re-irradiation was 51 months (range 6-185 months). The median re-irradiation dose delivered was 37.5 cobalt gray equivalent (CGE) in 15 fractions (range 6-50.4 CGE in 2-28 fractions) with 34 patients receiving this dose fractionation. Concurrent systemic therapy included bevacizumab (8), chemotherapy (5), immunotherapy (2) or none (28). Overall, 40 (93%) finished the planned course and three stopped early given progression. Median survival was 11.5 months for the full cohort (95% confidence interval: 6.8-13.6 months). For patients with glioblastoma, median survival was 6.4 months (95%CI 5.0-13.5 months). For patients without glioblastoma, median survival was 11.6 months (95%CI 9.2-34.3 months). Twelve patients (28%) developed symptomatic pseudoprogression/radiation necrosis, with ten requiring increased steroids and four requiring bevacizumab. CONCLUSIONS Proton re-irradiation was well tolerated in patients with recurrent glioma, with 6.4 and 11.6 month median survival estimates for glioblastoma and non-glioblastoma histologies, respectively. Symptomatic pseudoprogression/radiation necrosis was common. Further study is needed to determine whether proton re-irradiation has improved tolerability compared to photons.
INNV-31. ADOPTING TUMOR TREATING FIELDS (TTFIELDS) THERAPY FOR GLIOBLASTOMA AND OTHER SOLID CANCERS: CHALLENGES AND OPPORTUNITIES
Authors: Leonardo Lustgarten, Claudio Tatsui, Matthew Williams, Soma Sengupta, Eric Wong
Journal: Neuro-Oncology (2023)

Abstract Tumor Treating Fields (TTFields) are alternating electric fields generated by a wearable medical device (NovoTTF-200A), delivered to the tumor target by arrays placed on the skin. These fields have multiple biological effects on tumor cells, including mitotic disruption, dysregulated DNA repair, antimigratory effects, and stimulation of antitumor immune response. TTFields therapy was approved for recurrent and newly diagnosed glioblastoma, based on the randomized, pivotal EF-11 and EF-14 studies, respectively. Data from both studies demonstrated favorable outcomes, sustained quality of life, and tolerable safety profile. Side effects are limited to mostly manageable, mild to moderate skin reactions with no increased systemic toxicity. TTFields therapy is also approved for pleural mesothelioma and has met the primary endpoint in the pivotal LUNAR study for metastatic non-small cell lung cancer patients. Despite extensive preclinical data, positive clinical study outcomes, and favorable real-world evidence, adoption of TTFields therapy remains tepid. Here we discuss potential causes and possible solutions to treatment barriers. Based on extensive surveys in the field, we have identified several potential reasons. The first challenge is the perception that open-label studies are less rigorous since sham devices are not used per protocol. The purpose of sham treatments in trials is to minimize placebo effects and/or investigator bias, but RANO criteria is designed to guard against just that. Secondly, dissemination of knowledge underlying innovative therapies often takes time. Unlike chemotherapy and radiotherapy, the mechanistic aspects of TTFields are not typically included in oncology training. Lastly, the benefits of TTFields therapy may be difficult to appreciate due to the required chronic use during maintenance. Therefore, education, additional bench research, and future clinical studies are important for a better adoption of this increasingly important oncological option.
TMIC-53. TRANSGLUTAMINASE 2 EXPRESSION IN GLIOBLASTOMA: EVIDENCE FOR A ROLE IN EFFEROCYTOSIS
Authors: Ian Lorimer, Mara Elgafarawi, Margarita Lui, Filiz Sevinc, Alexa Leger, David Munoz, Jeffrey Keillor, John Woulfe
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma is the most common type of brain cancer in adults. It is currently incurable and there is a clear need for more effective treatments. The heterogeneity of this cancer and its ability to promote both local and systemic immunosuppression are major obstacles to the development of effective therapies. Previous studies have explored the use of transglutaminase 2 (TGM2) inhibitors for glioblastoma therapy. These studies focussed on TGM2 that is expressed in a subset of glioblastoma cells. We show here that glioblastoma-associated macrophages are a major source of TGM2 in glioblastoma tumours. Analysis of bulk and single cell RNAseq data showed that TGM2 mRNA was expressed at high levels in glioblastoma-associated macrophages. Immunohistochemical and immunofluorescence analysis of TGM2 expression was performed in a mouse xenograft model in which human mesenchymal subtype glioblastoma cells were grown intracerebrally in nude mice. In these xenograft tumours, glioblastoma cells were negative for TGM2 expression, while infiltrating macrophages were strongly positive. The most intense staining for TGM2 was observed in macrophages in the vicinity of necrotic regions. Apoptotic cells were frequently present within the necrotic regions and highly TGM2-positive macrophages were observed to be phagocytosing these. The same patterns of TGM2 expression were also observed in samples from glioblastoma patients. Consistent with a role in phagocytosis, TGM2 co-localized with the endosomal protein CD68 in glioblastoma-associated macrophages. The phagocytosis of apoptotic cells by macrophages, known as efferocytosis, is tolerogenic, both because it clears potentially antigenic material and because it induces an immunosuppressive phenotype in macrophages. As TGM2 has a previously established role in efferocytosis and autoimmunity suppression, our findings suggest that TGM2 has a role in maintaining the glioblastoma immunosuppressive environment and that its inhibition might enhance immunotherapy for this cancer.
NCOG-04. WHOLE-BRAIN STRUCTURAL CONNECTIVITY PREDICTS COGNITIVE DEFICITS IN PRETREATED PATIENTS WITH CNS WHO GRADE 3 OR 4 GLIOMAS
Authors: Michel Friedrich, Gabriele Stoffels, Christian Filss, Philipp Lohmann, Felix Mottaghy, Carolin Weiss Lucas, Maximilian Ruge, Nadim Shah, Svenja Caspers, Karl-Josef Langen, Gereon Fink, Norbert Galldiks, Martin Kocher
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioma patients frequently suffer from cognitive dysfunction potentially caused by tumor invasion or treatment effects. We hypothesized that cognitive functioning in pretreated glioma patients critically depends on the maintained structural connectivity of multiple brain networks. PATIENTS AND METHODS The study included 121 pretreated glioma patients (median age, 52 years; median ECOG score, 1; CNS WHO grade, 3 or 4) who had biopsy or resection plus chemoradiation as first-line therapy. Cognitive performance was assessed by ten tests in five main cognitive domains after a median time of 14 months (range, 1-214 months) after treatment initiation. Hybrid amino acid PET/MRI using the tracer O-(2-[18F]fluoroethyl)-L-tyrosine, a network-based cortical parcellation, and advanced tractography tools were used to generate whole-brain fiber count-weighted connectivity matrices. These matrices were applied to a machine learning-based model to identify predictive fiber connections, essential cortical nodes, and the networks underlying cognitive performance in the evaluated domains. RESULTS Compared to healthy controls (n=121), the cognitive scores were significantly lower in nine cognitive tests. For each test, a subset of connections between nodes (median number, 254; range, 32-542) was identified whose fiber count sum was related to the actual scores in a linear model (median R2, 0.37; range, 0.16-0.44). Leave-one-out cross-validation confirmed the model's generalizability in 7 of 10 tests (median correlation coefficient for predicted vs. observed scores, 0.47; range, 0.39-0.57). Critically involved cortical regions (≥ 10 adjacent predictive edges) included predominantly left-sided cortical nodes of the visual, somatomotor, dorsal/ventral attention, and default mode networks. Highly critical nodes (≥ 15-20 edges) included the default-mode network’s left temporal and bilateral posterior cingulate cortex. CONCLUSION These results suggest that the cognitive performance of pretreated glioma patients is strongly related to structural connectivity between multiple brain networks and depends on the integrity of known network hubs also involved in other neurological disorders.